Hepatitis delta virus (HDV) is an infectious subviral agent that can propagate in individuals infected with hepatitis B virus (HBV). It is the most severe form of chronic viral hepatitis in humans and ~20 million people worldwide are estimated to be chronically infected. In the U.S., the prevalence of chronic HDV infection is rising with recent data suggesting an urgent need for screening and treatment. There is no FDA approved treatment for HDV with current therapy consisting of pegylated interferon-alpha which only achieves cure in ~25% of patients. With limited treatment data available, understanding the dynamics of HDV infection and treatment response is in its infancy. The new prenylation inhibitor lonafarnib is the first direct acting anti-HDV agent being tested clinically, but pegylated interferon-lambda, Nucleic acid polymers and HDV/HBV entry inhibitor myrcludex B are also being investigated as anti-HDV therapies providing ongoing opportunities characterize HDV treatment dynamics and the mechanism of action of HDV antivirals and provide a window into the dynamics among HDV, HBV and host during co-infection. To gain insights into HDV-HBV-host-drug dynamics we have established an interdisciplinary team that includes clinicians who perform HDV treatment clinical trials, experimentalists to perform treatment and HDV/HBV coinfection studies in humanized mouse models and mathematical modelers to create mathematical/computational models to explain the patient and mouse data. The long-term goal of this proposal is to determine the MOA of anti-HDV drugs and optimal use of antiviral agents for the treatment of HDV.